N-Containing Na2VTi(PO4)3/C for Aqueous Sodium-Ion Batteries.

Phosphates featuring a 3D framework offer a promising alternative to aqueous sodium-ion batteries, known for their safety, cost-effectiveness, scalability, high power density, and tolerance to mishandling. Nevertheless, they often suffer from poor reversible capacity stemming from limited redox couples. Herein, N-containing Na2VTi(PO4)3 is synthesized for aqueous sodium-ion storage through multi-electron redox reactions. It demonstrates a capacity of 155.2 mAh g-1 at 1 A g-1 (≈ 5.3 C) and delivers an ultrahigh specific energy of 55.9 Wh kg-1 in a symmetric aqueous sodium-ion battery. The results from in situ X-ray diffraction analysis, ex situ X-ray photoelectron spectroscopy analysis, and first-principle calculations provide insights into the local chemical environment of sodium ions, the mechanisms underlying capacity decay during cycling, and the dynamics of ion and electron transfer at various states of charge. This understanding will contribute to the advancement of electrode materials for aqueous sodium-ion batteries.

Evaluating the Impact of Intracranial Volume Correction Approaches on the Quantification of Intracranial Structures in MRI: A Systematic Analysis.

BACKGROUND: In neuroscience, accurately quantifying individual brain regions in large cohorts is a challenge. Differences in intracranial structures can suggest functional differences, but they also reflect the effects of other factors. However, there is currently no standardized method for the correction of intracranial structure measurements. PURPOSE: To identify the optimal method to counteract the influence of total intracranial volume (TIV) and gender on the measurement of intracranial structures. STUDY TYPE: Prospective. POPULATION/SUBJECTS: One hundred forty-one healthy adult volunteers (70 male, mean age 21.8 ± 1.7 years). FIELD STRENGTH/SEQUENCE: T1-weighted 3D gradient-echo sequence at 3.0 T. ASSESSMENT: A radiologist with 5 years of work experience screened the raw images to exclude poor-quality images. Freesurfer then performed automated segmentation to obtain measurements of intracranial structures. Male-only, female-only, and TIV-matched sub-samples were created separately. Comparisons between the original data and these sub-samples were used to assess the effects of gender and TIV. Comparison the consistency between TIV-matched sample and corrected data that corrected by four methods: Proportion method, power-corrected proportion method, covariate regression method, and residual method. STATISTICAL TESTS: Cohen's d for examining group distribution disparities, t-tests for probing mean differences, correlation coefficients to assess the relationships between intracranial substructure measurements and TIV. Multiple comparison corrections were applied to the results. RESULTS: The correlation coefficients between TIV and the volumes of intracranial structures ranged from 0.033 to 0.883, with an average of 0.467. Thirty significant volume differences were found among 36 structures in the original sample, while no differences were observed in the TIV-matched sample. Among the four correction methods, the residual method had highest consistency (similarity 94.4%) with the TIV-matched group. DATA CONCLUSION: The variation in intracranial structure sizes between genders was largely attributable to TIV. The residual method offers a more accurate and effective approach for correcting the effects of TIV on intracranial structures. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Estimated health and economic impact of using high-dose influenza vaccine on respiratory and circulatory plus respiratory hospitalizations of older adults in Australia.

Background: Standard dose influenza vaccine provides moderate protection from infection, but with lower effectiveness among the elderly. High dose and adjuvanted vaccines (HD-TIV and aTIV) were developed to address this. This study aims to estimate the incremental health and economic impact of using HD-TIV (high dose trivalent vaccine) instead of aTIV (adjuvanted trivalent vaccine) on respiratory and circulatory plus respiratory hospitalizations of older people (≥65 years) in Australia. Methods: This is a modelling study comparing predicted hospitalization outcomes in people receiving HD-TIV or aTIV during an average influenza season in Australia. Hospitalization records of Australian adults ≥65 years of age from 01 April to 30 November during 15 influenza seasons (2002-2017 excluding 2009, which was a pandemic) were extracted from the Australian Institute of Health and Welfare [AIHW] and used to calculate hospitalisation rates during an average season. Relative vaccine effectiveness data for aTIV and HD-TIV were used to estimate morbidity burden related to influenza. Results: Between 2002 and 2017, the average respiratory hospitalization rate among older people during influenza season (April-November) was 3,445/100,000 population-seasons, with an average cost of AU$ 7,175 per admission. The average circulatory plus respiratory hospitalization rate among older Australian people during that time was 10,393/100,000 population-seasons, with an average cost of AU$ 7829 per admission. For older Australians, HD-TIV may avert an additional 6,315-9,410 respiratory admissions each year, with an incremental healthcare cost saving of AU$ 15.9-38.2 million per year compared to aTIV. Similar results were also noted for circulatory plus respiratory hospitalizations. Conclusions: From the modelled estimations, HD-TIV was associated with less economic burden and fewer respiratory, and circulatory plus respiratory hospitalizations than aTIV for older Australians.

Performance of serum neurofilament light chain in a wide spectrum of clinical courses of amyotrophic lateral sclerosis-a cross-sectional multicenter study.

BACKGROUND AND PURPOSE: The objective was to assess the performance of serum neurofilament light chain (sNfL) in amyotrophic lateral sclerosis (ALS) in a wide range of disease courses, in terms of progression, duration and tracheostomy invasive ventilation (TIV). METHODS: A prospective cross-sectional study at 12 ALS centers in Germany was performed. sNfL concentrations were age adjusted using sNfL Z scores expressing the number of standard deviations from the mean of a control reference database and correlated to ALS duration and ALS progression rate (ALS-PR), defined by the decline of the ALS Functional Rating Scale. RESULTS: In the total ALS cohort (n = 1378) the sNfL Z score was elevated (3.04; 2.46-3.43; 99.88th percentile). There was a strong correlation of sNfL Z score with ALS-PR (p < 0.001). In patients with long (5-10 years, n = 167) or very long ALS duration (>10 years, n = 94) the sNfL Z score was significantly lower compared to the typical ALS duration of <5 years (n = 1059) (p < 0.001). Furthermore, in patients with TIV, decreasing sNfL Z scores were found in correlation with TIV duration and ALS-PR (p = 0.002; p < 0.001). CONCLUSIONS: The finding of moderate sNfL elevation in patients with long ALS duration underlined the favorable prognosis of low sNfL. The strong correlation of sNfL Z score with ALS-PR strengthened its value as progression marker in clinical management and research. The lowering of sNfL in correlation with long TIV duration could reflect a reduction either in disease activity or in the neuroaxonal substrate of biomarker formation during the protracted course of ALS.

The Cost-Effectiveness of Vaccination of Older Adults with an MF59-Adjuvanted Quadrivalent Influenza Vaccine Compared to Other Available Quadrivalent Vaccines in Germany.

Enhanced quadrivalent influenza vaccines that include an adjuvant (aQIV) or a high dose of antigen (QIV-HD), which stimulate a stronger immune response in older adults than the standard vaccine (QIVe), are now approved. The objective of this research is to compare available vaccines and determine the cost-effectiveness of immunizing persons aged 65 years and above with aQIV compared to QIVe and QIV-HD in Germany. A compartmental transmission model calibrated to outpatient visits for influenza in Germany was used to predict the number of medically attended infections using the three vaccines. The rates of hospitalizations, deaths, and other economic consequences were estimated with a decision tree using German data where available. Based on meta-analysis, the rVE of -2.5% to 8.9% for aQIV versus QIV-HD, the vaccines are similar clinically, but aQIV is cost saving compared to QIV-HD (unit cost of EUR 40.55). All results were most sensitive to changes in vaccine effectiveness. aQIV may be cost-effective compared to QIVe depending on the willingness to pay for additional benefits in Germany. As aQIV and QIV-HD are similar in terms of effectiveness, aQIV is cost saving compared to QIV-HD at current unit prices.

Beyond "sex prediction": Estimating and interpreting multivariate sex differences and similarities in the brain.

Previous studies have shown that machine-learning (ML) algorithms can "predict" sex based on brain anatomical/ functional features. The high classification accuracy achieved by ML algorithms is often interpreted as revealing large differences between the brains of males and females and as confirming the existence of "male/female brains". However, classification and estimation are different concepts, and using classification metrics as surrogate estimates of between-group differences may result in major statistical and interpretative distortions. The present study avoids these distortions and provides a novel and detailed assessment of multivariate sex differences in gray matter volume (GMVOL) that does not rely on classification metrics. Moreover, appropriate regression methods were used to identify the brain areas that contribute the most to these multivariate differences, and clustering techniques and analyses of similarities (ANOSIM) were employed to empirically assess whether they assemble into two sex-typical profiles. Results revealed that multivariate sex differences in GMVOL: (1) are "large" if not adjusted for total intracranial volume (TIV) variation, but "small" when controlling for this variable; (2) differ in size between individuals and also depends on the ML algorithm used for their calculation (3) do not stem from two sex-typical profiles, and so describing them in terms of "male/female brains" is misleading.

Imaging features of histological subtypes of hepatocellular carcinoma: Implication for LI-RADS.

BACKGROUND & AIMS: The histopathological subtypes of hepatocellular carcinoma (HCC) are associated with distinct clinical features and prognoses. This study aims to report Liver Imaging Reporting and Data System (LI-RADS)-defined imaging features of different HCC subtypes in a cohort of resected tumours and to assess the influence of HCC subtypes on computed tomography (CT)/magnetic resonance imaging (MRI) LI-RADS categorisation in the subgroup of high-risk patients. METHODS: This retrospective institutional review board-approved study included patients with resected HCCs and available histopathological classification. Three radiologists independently reviewed preoperative CT and MRI exams. The readers evaluated the presence of imaging features according to LI-RADS v2018 definitions and provided a LI-RADS category in patients at high risk of HCC. Differences in LI-RADS features and categorisations were assessed for not otherwise specified (NOS-HCC), steatohepatitic (SH-HCC), and macrotrabecular-massive (MTM-HCC) types of HCCs. RESULTS: Two hundred and seventy-seven patients (median age 64.0 years, 215 [77.6%] men) were analysed, which involved 295 HCCs. There were 197 (66.7%) NOS-HCCs, 62 (21.0%) SH-HCCs, 23 (7.8%) MTM-HCCs, and 13 (4.5%) other rare subtypes. The following features were more frequent in MTM-HCC: elevated α-foetoprotein serum levels (p <0.001), tumour-in-vein (p <0.001 on CT, p ≤0.052 on MRI), presence of at least 1 LR-M feature (p ≤0.010 on CT), infiltrative appearance (p ≤0.032 on CT), necrosis or severe ischaemia (p ≤0.038 on CT), and larger size (p ≤0.006 on CT, p ≤0.011 on MRI). SH-HCC was associated with fat in mass (p <0.001 on CT, p ≤0.002 on MRI). The distribution of the LI-RADS major features and categories in high-risk patients did not significantly differ among the 3 main HCC subtypes. CONCLUSIONS: The distribution of LI-RADS major features and categories is not different among the HCC subtypes. Nevertheless, careful analysis of tumour-in-vein, LR-M, and ancillary features as well as clinico-biological data can provide information for the non-invasive diagnosis of HCC subtypes. LAY SUMMARY: In high-risk patients, the overall distribution of LI-RADS major features and categories is not different among the histological subtypes of hepatocellular carcinoma, but tumour-in-vein, presence of LR-M features, and ancillary features can provide information for the non-invasive diagnosis of hepatocellular carcinoma subtypes.

Non-invasive imaging criteria for the diagnosis of hepatocellular carcinoma in non-cirrhotic patients with chronic hepatitis B.

BACKGROUND & AIMS: Criteria defined by the European Association for the Study of the Liver (EASL) and Liver Imaging Reporting and Data System (LI-RADS) enable hepatocellular carcinoma (HCC) diagnosis based on imaging in cirrhosis. Non-cirrhotic patients require biopsy given the lower pre-test probability of HCC. The objective of our study was to assess the performance of EASL and LI-RADS criteria for the diagnosis of HCC in non-cirrhotic patients with chronic HBV infection. METHODS: This was a cross-sectional study performed at a referral center. We included all patients with HBV without cirrhosis with focal liver lesions who underwent contrast-enhanced CT or MRI at our clinic between 2005-2018. Studies were reviewed by 2 radiologists blinded to the diagnosis. RESULTS: We included 280 patients, median age was 56.8 (IQR 48.2-65.45) years and 223 (80%) were male. In 191 (79%) cases the lesion was found as a result of screening. Cirrhosis was excluded based on pathology in 252 (90%) cases. We assessed 338 nodules: 257 (76%) HCC, 40 (12%) non-HCC malignant lesions, and 41 (12%) benign lesions. EASL criteria and LR-5/LR-tumor-in-vein (TIV) categories had a 100% agreement in categorizing lesions as HCC, and 226 nodules (67%) were classified as HCCs. The sensitivity, specificity, positive predictive value, and negative predictive value were 82.1 (76.9-86.6), 81.5 (71.3-89.2), 93.4 (89.3-96.2), and 58.9 (49.2-68.1), respectively. When the pre-test probability of HCC is >70%, estimated as a PAGE-B score above 9, and EASL or LR-5/LR-TIV criteria are met, post-test probability would be >90%. CONCLUSIONS: EASL criteria and LR-5/LR-TIV categories show a positive predictive value in patients with HBV without cirrhosis that is comparable to that seen in patients with cirrhosis. These criteria can be used when the pre-test probability of HCC is >70%. LAY SUMMARY: Current guidelines recommend performing a biopsy to confirm the diagnosis of presumed hepatocellular carcinoma (HCC) in patients without cirrhosis. We showed that specific imaging criteria had a 100% agreement for categorizing lesions as HCC, with a positive predictive value of 93.4%. These imaging criteria could be used to diagnose HCC in HBV patients without cirrhosis with a pre-test probability of HCC of ≥70%, avoiding the need for a liver biopsy.

Morphological changes after cranial fractionated photon radiotherapy: Localized loss of white matter and grey matter volume with increasing dose.

PURPOSE: Numerous brain MR imaging studies have been performed to understand radiation-induced cognitive decline. However, many of them focus on a single region of interest, e.g. cerebral cortex or hippocampus. In this study, we use deformation-based morphometry (DBM) and voxel-based morphometry (VBM) to measure the morphological changes in patients receiving fractionated photon RT, and relate these to the dose. Additionally, we study tissue specific volume changes in white matter (WM), grey matter (GM), cerebrospinal fluid and total intracranial volume (TIV). METHODS AND MATERIALS: From our database, we selected 28 patients with MRI of high quality available at baseline and 1 year after RT. Scans were rigidly registered to each other, and to the planning CT and dose file. We used DBM to study non-tissue-specific volumetric changes, and VBM to study volume loss in grey matter. Observed changes were then related to the applied radiation dose (in EQD2). Additionally, brain tissue was segmented into WM, GM and cerebrospinal fluid, and changes in these volumes and TIV were tested. RESULTS: Performing DBM resulted in clusters of dose-dependent volume loss 1 year after RT seen throughout the brain. Both WM and GM were affected; within the latter both cerebral cortex and subcortical nuclei show volume loss. Volume loss rates ranging from 5.3 to 15.3%/30 Gy were seen in the cerebral cortical regions in which more than 40% of voxels were affected. In VBM, similar loss rates were seen in the cortex and nuclei. The total volume of WM and GM significantly decreased with rates of 5.8% and 2.1%, while TIV remained unchanged as expected. CONCLUSIONS: Radiotherapy is associated with dose-dependent intracranial morphological changes throughout the entire brain. Therefore, we will consider to revise sparing of organs at risk based on future cognitive and neurofunctional data.

Tumor in vein (LR-TIV) and liver imaging reporting and data system (LI-RADS) v2018: diagnostic features, pitfalls, prognostic and management implications.

Vascular invasion by hepatocellular carcinoma (HCC), also known as tumor in vein (TIV), indicates highly invasive tumor behavior and is also associated with poor outcome. Because a diagnosis of TIV precludes liver transplantation, knowledge of the imaging findings to differentiate between TIV and bland thrombus is key for proper patient management. Prior versions of liver imaging reporting and data system (LI-RADS) included presence of TIV as part of LR-5 criteria. However, even if HCC is the most common liver malignancy associated with TIV, other tumors can have vascular invasion and may occur in cirrhotic patients. For these reasons, in LI-RADS v2017 LR-TIV has been introduced as a new different diagnostic category. The aim of this article is to discuss the diagnostic criteria of LR-TIV according to LI-RADS v2018 and analyze potential pitfalls encountered on daily clinical practice. Indeterminate cases and how to manage them will also be discussed.

Immunogenicity and safety levels of inactivated quadrivalent influenza vaccine in healthy adults via meta-analysis.

Objective: The aim of the current study was to evaluate immunogenicity and safety levels of human inactivated quadrivalent influenza vaccine (QIV) which includes two A strains (A/H1N1, A/H3N2) and two B lineages (B/Victoria, B/Yamagata) in healthy adults via meta-analysis. Methods: Searches were conducted in PubMed, Cochrane Library, ClinicalTrials.gov, and EMBASE databases published in 2011-2020 according to inclusion and exclusion criteria. The purpose was to collect and perform meta-analysis of related randomized clinical trial (RCT) data concerning safety and immunogenicity levels of human QIV compared with inactivated trivalent influenza vaccine (TIV). Results: A total of 9 literatures were included. There was no significant difference in the seroconversion(SCR) and seroprotection(SPR) between QIV and TIV for influenza A strains (A/H1N1, A/H3N2) and the B lineage included in the TIV. QIV showed superior efficacy for the B lineage not included in the TIV: SCR RR of 2.20 (95%CI: 1.44-3.37, p = .0003) and SPR RR of 1.34 (95%CI: 1.10-1.63, p = .004) for B/Victoria, and SCR RR of 1.88 (95%CI: 1.53-2.31, p < .00001) and SPR RR of 1.11 (95%CI: 1.03-1.19, p = .006) for B/Yamagata, respectively. There were no significant differences between QIV and TIV for local and systemic adverse events(AE) post-vaccination. Conclusion: In adults 18-64 years old, QIV not only produced similar immunogenicity and safety levels to TIV, but also had better immunogenicity against influenza B vaccine strains not included in TIV.

Cost-Effectiveness Analysis of Switching from Trivalent to Quadrivalent Seasonal Influenza Vaccine in Argentina.

The burden of seasonal influenza disease in Argentina is considerable. The cost-effectiveness of trivalent (TIV) versus quadrivalent influenza vaccine (QIV) in Argentina was assessed. An age-stratified, static, decision-tree model compared the costs and benefits of vaccination for an average influenza season. Main outcomes included: numbers of influenza cases; general practitioner (GP) visits; complicated ambulatory cases; hospitalizations; deaths averted; and costs per quality-adjusted life years (QALYs) gained. Epidemiological data from Argentina for 2014-2019 were used to determine the proportion of A and B strain cases, and the frequency of mismatch between vaccine and circulating B strains. To manage uncertainty, one-way and probabilistic sensitivity analyses were performed. Switching from TIV to QIV would prevent 19,128 influenza cases, 16,164 GP visits, 2440 complicated ambulatory cases, 524 hospitalizations, and 82 deaths. Incremental cost-effectiveness ratios (ICERs) per QALY were 13,590 and 11,678 USD from the payer's and societal perspectives, respectively. The greatest health benefits and direct medical cost savings would occur in ≥ 65-year-olds. One-way sensitivity analyses demonstrated the principal drivers of ICER to be vaccine acquisition costs, environmental B strain predominance, and B strain mismatch. Introducing QIV in Argentina would be beneficial and cost-effective relative to TIV, particularly in older adults.

Non-sterilizing, Infection-Permissive Vaccination With Inactivated Influenza Virus Vaccine Reshapes Subsequent Virus Infection-Induced Protective Heterosubtypic Immunity From Cellular to Humoral Cross-Reactive Immune Responses.

Conventional influenza vaccines aim at the induction of virus-neutralizing antibodies that provide with sterilizing immunity. However, influenza vaccination often confers protection from disease but not from infection. The impact of infection-permissive vaccination on the immune response elicited by subsequent influenza virus infection is not well-understood. Here, we investigated to what extent infection-permissive immunity, in contrast to virus-neutralizing immunity, provided by a trivalent inactivated virus vaccine (TIV) modulates disease and virus-induced host immune responses after sublethal vaccine-matching H1N1 infection in a mouse model. More than one TIV vaccination was needed to induce a serum HI titer and provide sterilizing immunity upon homologous virus infection. However, single TIV administration provided infection-permissive immunity, characterized by lower viral lung titers and faster recovery. Despite the presence of replicating virus, single TIV vaccination prevented induction of pro-inflammatory cyto- and chemokines, alveolar macrophage depletion as well as the establishment of lung-resident B and T cells after infection. To investigate virus infection-induced cross-protective heterosubtypic immune responses in vaccinated and unvaccinated animals, mice were re-infected with a lethal dose of H3N2 virus 4 weeks after H1N1 infection. Single TIV vaccination did not prevent H1N1 virus infection-induced heterosubtypic cross-protection, but shifted the mechanism of cross-protection from the cellular to the humoral branch of the immune system. These results suggest that suboptimal vaccination with conventional influenza vaccines may still positively modulate disease outcome after influenza virus infection, while promoting humoral heterosubtypic immunity after virus infection.

Comparison of autophagy inducibility in various tyrosine kinase inhibitors and their enhanced cytotoxicity via inhibition of autophagy in cancer cells in combined treatment with azithromycin.

Tyrosine kinase inhibitors (TKIs) induce autophagy in many types of cancer cells. We previously reported that gefitinib (GEF) and imatinib (IMA) induce autophagy in epidermal growth factor receptor (EGFR) knock-out A549 and non-BCR-ABL-expressing leukemia cell lines, respectively. This evidence suggests that TKI-induced autophagy is independent of the original target molecules. The present study compared the autophagy-inducing abilities of various TKIs, regardless of their targets, by quantitative autophagy flux assay. We established stable clones expressing the GFP-LC3-mCherry-LC3ΔG plasmid in A549, PC-9, and CAL 27 cell lines and assessed autophagy inducibility by monitoring the fluorescent ratios of GFP-LC3 to mCherry-LC3ΔG using an IncuCyte live cell imaging system during exposure to TKIs viz; GEF, osimertinib (OSI), lapatinib (LAP), lenvatinib (LEN), sorafenib (SOR), IMA, dasatinib (DAS), and tivantinib (TIV). Among these TKIs, DAS, GEF, and SOR exhibited prominent autophagy induction in A549 and PC-9 cells. In CAL 27 cells, IMA, SOR, and LEN, but not GEF, TIV, or OSI, exhibited autophagy induction. In the presence of azithromycin (AZM), which showed an inhibitory effect on autophagy flux, TKIs with prominent autophagy inducibility exhibited enhanced cytotoxicity via non-apoptotic cell death relative to effects of TKI alone. Therefore, autophagy inducibility of TKIs differed in the context of cancer cells. However, once induced, they appeared to have cytoprotective functions. Thus, blocking TKI-induced autophagy with AZM may improve the therapeutic effect of TKIs in cancer cells.

The Effect of Maternal Immunisation During Pregnancy on Infant Vaccine Responses.

INTRODUCTION: Immunisation during pregnancy to protect infants against tetanus, pertussis and influenza is recommended in many countries. However, maternal antibodies can interfere with infant vaccine responses. We investigated the effect of antenatal diphtheria-tetanus-acellular pertussis (dTpa) and trivalent inactivated influenza (TIV) immunisation on specific and heterologous antibody responses to routine immunisations given in the first year of life. METHODS: In total, 471 healthy infants were included. At 7 and 13 months of age, antibodies to the primary course of routine vaccines given at 6 weeks, 4 and 6 months of age (pertussis (pertussis toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN)), polio (type 1, 2, 3), Haemophilus influenzae type b (Hib), pneumococcus (serotype 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F)) were measured, and at 13 months of age, antibodies to the 12-month routine vaccines (Hib, meningococcus C, measles, mumps and rubella). The seroprotection rates for each vaccine and the geometric mean concentrations (GMC) of antibodies were compared between infants whose mothers did or did not receive dTpa or TIV immunisation during pregnancy. RESULTS: A total of 369 infants were included in the final analysis. Maternal dTpa immunisation was associated with reduced antibody responses to both specific (diphtheria and pertussis) and heterologous (polio and pneumococcus) vaccine antigens. This effect was stronger for persistence of antibodies at 13 months of age than it was at 7 months of age. At 7 months of age, adjusted average antibody concentrations were significantly lower for diphtheria, pertussis (PT, FHA, PRN) and polio type 2, and at 13 months of age, for diphtheria, pertussis (PT, FHA, PRN), polio type 1-3 and pneumococcal serotypes 1, 4, 5, 6A, 6B, 7F, 18C and 23F. Additionally, at 13 months of age, seroprotection rates for diphtheria, PT, pneumococcal serotype 1, 6A and 6B were significantly lower in infants after maternal dTpa immunisation. In contrast, for Hib, in infants with maternal dTpa immunisation, the adjusted average antibody concentration and the seroprotection rate were higher, particularly at 7 months of age. Maternal TIV immunisation had minimal effect on infant vaccine responses. CONCLUSION: Whilst maternal immunisation protects infants in the first few months of life, it might interfere with both specific and heterologous (unrelated) vaccines responses in infants. RESEARCH IN CONTEXT: Evidence before this study: Maternal immunisation during pregnancy helps to protect infants during the period before they complete their primary immunisations. It has been proven to be safe and beneficial. However, pre-existing maternal antibodies can influence antibody responses following infant immunisation, an effect called 'blunting'. Previous studies have investigated the influence of dTpa but not influenza immunisation during pregnancy on infant vaccine responses. The majority of studies investigated antibody concentrations only to the specific vaccine antigens included in the maternal immunisation, and there is scarce data available on heterologous vaccine responses, particularly pneumococcal responses.Added value of this study: In this study, we have shown that maternal dTpa immunisation during pregnancy is associated with reduced antibody responses to both specific (diphtheria and pertussis) and heterologous (polio and pneumococcus) vaccine antigens. This effect is stronger for persistence of antibodies at 13 months of age than after primary immunisation at 7 months of age. In contrast, for Hib, in infants with maternal dTpa immunisation, antibody concentrations are higher, particularly at 7 months of age. Maternal TIV immunisation has minimal effect on infant vaccine responses.Implications of all the available evidence: Whilst maternal immunisation protects infants in the first few months of life, it might interfere with both specific and heterologous (unrelated) vaccines responses in infants. As most vaccines induce very high antibody responses, small differences in antibody concentrations may not be of clinical significance. However, since maternal immunisation during pregnancy also influences seroprotection rates, strategies, such as additional booster doses in the second year of life, particularly for pertussis and pneumococcus, might need to be considered to address this.

TIV Vaccination Modulates Host Responses to Influenza Virus Infection that Correlate with Protection against Bacterial Superinfection.

BACKGROUND: Influenza virus infection predisposes to secondary bacterial pneumonia. Currently licensed influenza vaccines aim at the induction of neutralizing antibodies and are less effective if the induction of neutralizing antibodies is low and/or the influenza virus changes its antigenic surface. We investigated the effect of suboptimal vaccination on the outcome of post-influenza bacterial superinfection. METHODS: We established a mouse vaccination model that allows control of disease severity after influenza virus infection despite inefficient induction of virus-neutralizing antibody titers by vaccination. We investigated the effect of vaccination on virus-induced host immune responses and on the outcome of superinfection with Staphylococcus aureus. RESULTS: Vaccination with trivalent inactivated virus vaccine (TIV) reduced morbidity after influenza A virus infection but did not prevent virus replication completely. Despite the poor induction of influenza-specific antibodies, TIV protected from mortality after bacterial superinfection. Vaccination limited loss of alveolar macrophages and reduced levels of infiltrating pulmonary monocytes after influenza virus infection. Interestingly, TIV vaccination resulted in enhanced levels of eosinophils after influenza virus infection and recruitment of neutrophils in both lungs and mediastinal lymph nodes after bacterial superinfection. CONCLUSION: These observations highlight the importance of disease modulation by influenza vaccination, even when suboptimal, and suggest that influenza vaccination is still beneficial to protect during bacterial superinfection in the absence of complete virus neutralization.

Sex differences in gray matter volume: how many and how large are they really?

BACKGROUND: Studies assessing volumetric sex differences have provided contradictory results. Total intracranial volume (TIV) is a major confounding factor when estimating local volumes of interest (VOIs). We investigated how the number, size, and direction of sex differences in gray matter volume (GMv) vary depending on how TIV variation is statistically handled. METHODS: Sex differences in the GMv of 116 VOIs were assessed in 356 participants (171 females) without correcting for TIV variation or after adjusting the data with 5 different methods (VBM8 non-linear-only modulation, proportions, power-corrected-proportions, covariation, and the residuals method). The outcomes obtained with these procedures were compared to each other and to those obtained in three criterial subsamples, one comparing female-male pairs matched on their TIV and two others comparing groups of either females or males with large/small TIVs. Linear regression was used to quantify TIV effects on raw GMv and the efficacy of each method in controlling for them. RESULTS: Males had larger raw GMv than females in all brain areas, but these differences were driven by direct TIV-VOIs relationships and more closely resembled the differences observed between individuals with large/small TIVs of sex-specific subsamples than the sex differences observed in the TIV-matched subsample. All TIV-adjustment methods reduced the number of sex differences but their results were very different. The VBM8- and the proportions-adjustment methods inverted TIV-VOIs relationships and resulted in larger adjusted volumes in females, promoting sex differences largely attributable to TIV variation and very distinct from those observed in the TIV-matched subsample. The other three methods provided results unrelated to TIV and very similar to those of the TIV-matched subsample. In these datasets, sex differences were bidirectional and achieved satisfactory replication rates in 19 VOIs, but they were "small" (d < ∣0.38∣) and most of them faded away after correcting for multiple comparisons. CONCLUSIONS: There is not just one answer to the question of how many and how large the sex differences in GMv are, but not all the possible answers are equally valid. When TIV effects are ruled out using appropriate adjustment methods, few sex differences (if any) remain statistically significant, and their size is quite reduced.

Prebiotic oligosaccharides in early life alter gut microbiome development in male mice while supporting influenza vaccination responses.

Beneficial modulation of the gut microbiota is an attractive therapeutic approach to improve the efficacy of vaccine-induced immunity. In this study, mice were supplemented with the prebiotic milk oligosaccharide 2'-fucosyllactose (2'FL) as well as a complex mixture of immune modulatory prebiotic short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS) from different stages in early life. Adult mice were vaccinated with trivalent influenza vaccine (TIV) and both development of the gut microbiota and antibody-mediated vaccine responses were followed over time. Within the control group, female mice demonstrated a larger antibody response to TIV vaccination than male mice, which was accompanied by enhanced cytokine production by splenocytes and a higher percentage of plasma cells in skin draining lymph nodes. In addition, the prebiotic diet improved vaccine-specific antibody responses in male mice. Introduction of prebiotics into the diet modulated the gut microbiota composition and at the genus level several bacterial groups showed a significant interaction effect which potentially contributed to the immunological effects observed. This study provides insight in the effect of scGOS/lcFOS/2'FL in influenza vaccination antibody production.

Interferon alpha receptors and STAT1 as therapy predictors of a sustained virological response in hepatitis C/B co-infection.

OBJECTIVE: : To determine the expression of interferon alpha receptors 1 and 2 along with signal transducer and activator of transcription-1 in peripheral blood mononuclear cells of both hepatitis C mono-infected and hepatitis C and B co-infected patients, and to assess whether these targeted genes predict sustained virological response to interferon therapy. METHODS: This cross-sectional study was carried out at the Army Medical College, Rawalpindi, Pakistan, from January 2012 to December 2015, and comprised hepatitis C mono-infected and hepatitis C and B co-infected patients. The patients were divided into groups 1 and 2. Group-1a and group-2a consisted of mono-infected and co-infected sustained responders, while group-1b and group-2b had mono-infected and co-infected non sustained responders. Peripheral blood mononuclear cells from healthy controls were also quantified for these subunits. Target gene expressions were studied by retro-transcription of respective messenger ribonuclieic acid extracted from the cells followed by polymerase chain reaction amplification. RESULTS: Of the 191 subjects, there were 20(10.5%) in group-1a, 35(18.3%) in group-2a, 65(34%) in group-1b and 51(26.7%) in group-2b. The remaining 20(10.5%) were controls. Overall, 106 (55.5%) were males and 85 (44.5%) were females. Interferon alpha receptor 1 expression in groups 1a and 2a was significantly higher compared to groups 1b (p=0.018) and 2b (p 0.031). Signal transducer and activator of transcription-1 protein expression showed no significant difference (p=0.062 and p=0.519). No difference in expression was measured between the two sets of groups with regard to interferon alpha receptor 2 expression (p=0.278 and p=0.590). CONCLUSIONS: Our results show that levels of IFNAR-1 mRNA expression may be a good predictor for IFN-related anti-viral activity in both HCV mono infected and HCV/HBV co-infected patients.

Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets.

Alzheimer's disease (AD) is characterized by an accumulation of ß-amyloid (Aß42) accompanied by brain atrophy and cognitive decline. Several recent studies have shown that Aß42 accumulation is associated with gray matter (GM) changes prior to the development of cognitive impairment, in the so-called preclinical stage of the AD (pre-AD). It also has been proved that the GM atrophy profile is not linear, both in normal ageing but, especially, on AD. However, several other factors may influence this association and may have an impact on the generalization of results from different samples. In this work, we estimate differences in rates of GM volume change in cognitively healthy elders in association with baseline core cerebrospinal fluid (CSF) AD biomarkers, and assess to what these differences are sample dependent. We report the dependence of atrophy rates, measured in a two-year interval, on Aß42, computed both over continuous and categorical values of Aß42, at voxel-level (p < 0.001; k < 100) and corrected for sex, age and education. Analyses were performed jointly and separately, on two samples. The first sample was formed of 31 individuals (22 Ctrl and 9 pre-AD), aged 60-80 and recruited at the Hospital Clinic of Barcelona. The second sample was a replica of the first one with subjects selected from the ADNI dataset. We also investigated the dependence of the GM atrophy rate on the basal levels of continuous p-tau and on the p-tau/Aß42 ratio. Correlation analyses on the whole sample showed a dependence of GM atrophy rates on Aß42 in medial and orbital frontal, precuneus, cingulate, medial temporal regions and cerebellum. Correlations with p-tau were located in the left hippocampus, parahippocampus and striatal nuclei whereas correlation with p-tau/Aß42 was mainly found in ventral and medial temporal areas. Regarding analyses performed separately, we found a substantial discrepancy of results between samples, illustrating the complexities of comparing two independent datasets even when using the same inclusion criteria. Such discrepancies may lead to significant differences in the sample size needed to detect a particular reduction on cerebral atrophy rates in prevention trials. Higher cognitive reserve and more advanced pathological progression in the ADNI sample could partially account for the observed discrepancies. Taken together, our findings in these two samples highlight the importance of comparing and merging independent datasets to draw more robust and generalizable conclusions on the structural changes in the preclinical stages of AD.